Research Area

Summary of Current Work

Translational application of well-supported, fundamental ovarian cancer research to potential improved clinical outcome for ovarian cancer patients cannot be emphasized enough. Every year in Canada alone, about 2400 women will be diagnosed with ovarian cancer, and 1700 women will die of this disease (2007 Canadian Cancer Statistics). This is entirely due to the lack of reliable early detection methods combined with poor therapeutic management of recurrent disease. Taken together, my proposed research program will further elucidate the functional implications of altered bone morphogenetic protein (BMP) signalling in epithelial ovarian cancer (EOC) cell adhesion and metastasis and ID proto-oncogene expression in ovarian cancer initiation and progression. I will also utilize important, current techniques which are critically relevant to ovarian cancer research, including culturing and characterization of primary human ovarian surface epithelial (OSE) and EOC cells, as well as the more recently-established transgenic mouse modelling of this disease. I foresee the direct translational potential of my proposed research via the rapid initiation of key collaborative research efforts with basic and clinical scientists of the Translational Ovarian Cancer Research Group of the London Regional Cancer Program and the University of Western Ontario. More importantly, I will aid in establishing new research endeavours into the field of ovarian cancer with basic scientists of the LRCP, as well as participate in clinical research projects with clinicians of the Division of Gynaecologic Oncology.

Ovarian cancer is the sixth most prevalent cancer amongst women and is the most lethal of the gynecological malignancies, yet the current knowledge of the molecular basis for this disease is still quite deficient. Thus, the discovery and thorough examination of molecules potentially implicated in ovarian cancer pathogenesis is an ongoing pursuit. To this end, I have identified that active bone morphogenetic protein (BMP)-4 signalling leads to the direct and heightened upregulation of ID1 and ID3 proto -oncogenes in human epithelial ovarian cancer (EOC) cells in comparison with normal human ovarian surface epithelial (OSE) cells. The ID genes encode helix-loop-helix proteins that bind to and inhibit the function of transcription factors; ID gene overexpression has been observed in human cancers, including ovarian cancer, and is correlated with increased metastatic potential and poor patient prognosis. My analyses addressing the mechanism controlling BMP4-mediated regulation of ID3 gene expression in EOC cells has provided additional clues explaining both the similar and differential regulation of the ID1 and ID3 proto -oncogenes that may contribute to ovarian tumorigenesis . Thus, I hypothesize that ID1 & ID3 gene overexpression contributes to human ovarian cancer pathogenesis . To directly address this research question, my studies will focus on the following:

To carry out this research program, I will utilize several different research tools and technologies which I have developed during my postdoctoral studies. For example, ectopic overexpression of Id1 and Id3 proteins, and knockdown studies using RNA interference technology, will be performed using recombinant adenoviral vectors. I will continue to isolate and use primary human normal OSE and ascites-derived EOC cells via the establishment of collaborative efforts with the clinicians of the Division of Gynaecologic Oncology. My in vivo analyses will entail adenovirus transduction of intact mouse OSE cells by intrabursal virus administration under the ovarian bursa, as well as intraperitoneal xenografting of stably-transfected cell lines into nude mice. The results from these studies will clearly demonstrate whether Id1 and Id3 play an important role in human ovarian cancer initiation and progression. As part of the collaborative research efforts within the Translational Ovarian Cancer Research Program, transgenic mouse strains will be generated (Dr. Gabriel DiMattia as co-investigator) to develop accurate mouse models of human ovarian cancer pathogenesis.

To carry out this research program, primary human normal OSE and ascites-derived EOC cells will be used. Activation of BMP signalling will entail treating with recombinant BMP ligands, as well as utilizing adenoviral vectors which express constitutively-active BMP type I receptors. Virus-mediated transduction of EOC cells with short-hairpin RNA expression constructs targeting ID1 and ID3 mRNA will be performed, as well as targeted knockdown of Smad4. Cell culture studies will involve both standard two-dimensional cultures as well as three-dimensional culturing of EOC cell spheroids. Modelling spheroid growth in culture will allow the direct study of BMP signalling on cell-cell interactions that may be involved in mediating EOC cell clustering that occurs in patient ascites. Most importantly, as consistently laid out in my overall ovarian cancer research program, I will use parallel cell culture and in vivo mouse modelling systems to directly address the functional role of BMP signalling on EOC cell adhesion to approximate the physiological and pathological context of ovarian cancer in patients.